This application in response to the RFA for the Tumor Microenvironment Network (TMEN) will focus on mouse models of cancer initiation and progression, particularly in the breast and lung and involving both transplantable and autochthonous (i.e. spontaneous endogenous) tumors. The applicant group is multidisciplinary, involving investigators expert in mouse models, cancer cell biology, molecular imaging and proteomics. The individual subprojects will focus on specific components of the tumor microenvironment;cells, secreted factors and extracellular matrix (collectively termed stroma), as well as on the nature of the immune response to cancer. We will investigate the following topics:- 1. stromal influences on why and how tumor cells initially become invasive and metastatic as a consequence of stromal effects at the site of the primary tumor. 2. microenvironmental effects that can suppress or enhance the seeding, survival and growth of metastases at secondary sites. 3. the identity and origins of stromal cells (mesenchymal and hematopoietic) induced at, or recruited to, the site of a primary tumor, how they are recruited, and how they affect the progression of the tumor 4. the nature of immune surveillance of autochthonous tumors 5. the nature of different tumor extracellular matrices (ECMs) and interactions of both tumor and stromal cells with ECM 6. we will further develop novel imaging probes and methods to detect, track and ablate different subsets of stromal cells in mouse models of cancer. 7. we will use lentiviral-mediated RNA interference both to initiate autochthonous tumors and to manipulate the functions of both tumor and stromal cells. It is becoming increasingly recognized that tumor cells do not progress to malignancy in isolation - the microenvirnment of the tumor can either enhance or suppress tumor growth and progression. This program will provide new information and novel technological approaches to questions concerning the effects of the surrounding microenvironment in which tumors develop. It is expected that new insights from this research will offer novel approaches to intervene in the progression of tumors to malignancy.